Anti-allergic aminooxanilic acids and esters

ABSTRACT

Pharmaceutical composition having as the active agent a compound of the formula ##STR1## wherein R is hydrogen, a physiologically acceptable metal or amine cation and alkyl of one to eight carbon atoms inclusive, useful for preventing allergic manifestations in sensitized mammals.

BRIEF SUMMARY OF THE INVENTION

It has now been discovered that novel compositions of Formula 1 areuseful in the prophylactic treatment of sensitized humans and animalsfor allergy and anaphylactic reactions of a reagin or non-reaginmediated nature. The compounds are formulated with pharmaceuticalcarriers for oral, parenteral or inhalation means of administration.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with this invention, there are provided pharmaceuticalcompositions, hereafter referred to as Group A, having an anti-allergyeffective amount of a compound of the formula ##STR2## WHEREIN R ishydrogen, a physiologically acceptable metal or amine cation, or alkylof one to eight carbon atoms in association with a pharmaceuticalcarrier.

A further group of compositions, hereafter referred to as Group B, arethe compositions of Group A wherein R is alkyl of one to eight carbonatoms, inclusive.

Another group of compositions hereafter referred to as Group C are thoseof Group B suitable for oral means of administration.

A further group of compositions hereafter referred to as Group D are thecompositions of Group C having a solid pharmaceutical carrier.

Another group of compositions, hereafter referred to as Group E, are thecompositions of Group C having a non-aqueous liquid carrier.

A further aspect of the invention is a method of prophylacticallypreventing the manifestation of allergy of a reagin or non-reaginmediated nature, particularly asthma, allergic rhinitis, urticaria, foodallergy or anaphylactoid reactions comprising the administration of acompound of FIG. 1 in association with a pharmaceutical carrier to amammal in need of such treatment.

The oral delivery system is preferred.

The compound wherein R is ethyl is preferred.

As employed in the above disclosure and throughout the specification andclaims, the phrase "alkyl of one to eight carbon atoms, inclusive" meansmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomersthereof. Illustrative examples of isomers are isopropyl, tert butyl,neopentyl, 2,2-dimethylbutyl, 2-methylhexyl and 2,2,4-trimethylpentyl.

The phrase "physiologically acceptable amine salt" refers to amineswhich are accepted by mammals in an essentially non-toxic manner whenadministered to mammals in conjunction with the acid moiety of theinvention. Illustrative of the amines are those derived from primary,secondary or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, triethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, adamantylamines, and likealiphatic, cycloaliphatic, and araliphatic amines containing up to andincluding about eighteen carbon atoms as well as heterocyclic amines,e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkylderivatives thereof, e.g., 1-methylpiperidine, 4-ethylmorpholine,1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine,2-methylpiperidine, and the like, as well as amines containingwater-solubilizing or hydrophilic groups, e.g., mono-, di-, andtriethanolamine, ethyldiethanolamine, N-butylethanolamine,2-amino-1-butanol, 2-amino-1-ethyl-1,3-propanediol,2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)diethanolamine, galactamine,N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine,epinephrine, procaine, and the like.

The term "physiologically acceptable metal" includes alkali metals suchas sodium and potassium, alkaline earth metals such as calcium andmagnesium and other acceptable metals such as aluminum.

The compounds of the invention are readily prepared by methods wellknown in the art. The m-nitro-aniline is reacted with an oxalyl halidepreferably ethyl oxalyl chloride in a suitable solvent and base to formthe m-nitro oxamate. An alternative method of preparing the oxamate isto react the m-nitroaniline with a dialkyl oxalate, preferably diethyloxalate, in neat solution or with an additional solvent if necessary.

When using an alkyl oxalyl halide, reaction is carried out in base andsolvent at standard conditions. Examples of suitable solvents aredimethylformamide, dioxane, and tetrahydrofuran. Appropriate basesinclude triethylamine, N-methylmorpholine, dimethylpiperazine, andN-methylpiperidine. When the dialkyl oxalate is employed, the aminostarting material is heated together with the dialkyl oxalate or anadditional solvent such as a xylene or diphenyl ether if desired,thereby forming the oxamate. The temperature is from about 25° C. to thereflux temperature of the system.

After preparing the ester the nitro is reduced to an amino functionunder standard conditions, for example, catalytic means such aspalladium on charcoal in the presence of hydrogen or by chemical meanssuch as iron and hydrochloric acid.

At this point of the synthetic pathway, the oxamate can betransesterified to other esters and/or converted to the acid byhydrolysis and thence to the metal or amine salts by standard methods.

The oxamate is readily converted to the oxamic acid by using dilute basesuch as sodium hydroxide, potassium hydroxide or potassium carbonate attemperatures ranging from about 25° to about 100° C., followed byaddition of acid.

Following are examples of the invention. These examples are intended toexemplify but not to limit the invention.

EXAMPLE 1--Ethyl 3'-amino-oxanilate a. Ethyl 3'-nitro-oxanilate

To a stirred solution of 39.5 g. (0.286 moles) of m-nitroaniline and36.52 g. (0.358 moles) of triethylamine in 50 ml. of drydimethylformamide and 250 ml. of dry ethyl acetate cooled to 0° is addeddropwise 49.0 g. (0.358 moles) of ethyl oxalyl chloride. The reactionmixture is allowed to stand at room temperature overnight.

The precipitate is removed by filtration. The precipitate is shaken witha mixture of ethyl acetate and water. The ethyl acetate extracts arecombined with the original filtrate and the mixture dried over magnesiumsulfate. The drying agent is removed, the solvents removed bydistillation in vacuo and the residue recrystallized from ethanol. Thereis obtained 43.5 g. (64%) of yellow needles that melt at 148°-9° C.

Analysis Calc'd for: C₁₀ H₁₀ N₂ O₅ : C, 50.42; H, 4.23; N, 11.76%.Found: C, 50.44; H, 4.28; N, 11.72%.

b. Ethyl 3'-amino-oxanilate

A suspension of 13.65 gm. (0.057 mole) of ethyl-3'-nitro-oxanilate, 150ml. of ethanol and 1 g. of 10% palladium/charcoal is hydrogenated on aParr apparatus at a temperature of 40°-45° C. The catalyst is removed byfiltration and the filtrate evaporated to dryness. 10.95 grams ofethyl-3'-amino-oxanilate are obtained, M.P. 112°-115° C.

Analysis Calc'd for: C₁₀ H₁₂ N₂ O₃ : C, 57.68; H, 5.81; N, 13.45. Found:C, 57.45; H, 5.92; N, 13.61.

EXAMPLE 2

3'-aminooxanilic acid monohydrate is prepared by the procedure of W. A.Jacobs and M. Heidelberger [J. Amer. Chem. Soc. 39, 1447 (1917)].

EXAMPLE 3--Tris(hydroxymethyl)methylammonium 3'-aminooxanilate

To a mixture of 3'-aminooxanilic acid monohydrate in 50 ml. of anhydrousethanol is added an equivalent amount of tris(hydroxymethyl)aminomethane (THAM). The mixture is stirred for 3 hours and theanhydrous ethanol removed by distillation under diminished pressure.

EXAMPLE 4--Sodium 3'-aminooxanilate

To a mixture of 10 g. of 3'-aminooxanilic acid monohydrate and 50 ml. ofwater is added an equivalent amount of sodium hydroxide. The solution isevaporated to dryness and the residue is triturated with anhydrousethanol.

EXAMPLE 5

Following the procedures of the specification and the above examples,the following compounds are prepared:

n-Propyl 3'-amino oxanilate

n-Butyl 3'-amino oxanilate

n-Pentyl 3'-amino oxanilate

n-Hexyl 3'-amino oxanilate

n-Heptyl 3'-amino oxanilate

n-Octyl 3'-amino oxanilate

Isopropyl 3'-amino oxanilate

Tert. butyl 3'-amino oxanilate

Neopentyl 3'-amino oxanilate

2,2-dimethylbutyl 3'-amino oxanilate

2-methylhexyl 3'-amino oxanilate

Isooctyl 3'-amino oxanilate

Potassio 3'-amino oxanilate

Triethylammonium 3'-amino oxanilate

The compositions of the present invention are presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, eye drops, oral solutions or suspensions, andoil-in-water and water-in-oil emulsions containing suitable quantitiesof the compound of Formula 1. The preferred method of administration isorally utilizing an ester of the active compound.

For oral administration, either solid or fluid unit dosage forms can beprepared. For preparing solid compositions such as tablets, the compoundof Formula 1 is mixed with conventional ingredients such as talc,magnesium stearate, dicalcium phosphate, magnesium aluminum silicate,calcium sulfate, starch, lactose, acacia, methylcellulose, andfunctionally similar materials as pharmaceutical diluents or carriers.Capsules are prepared by mixing the compound with an inertpharmaceutical diluent and filling the mixture into a hard gelatincapsule of appropriate size. Soft gelatin capsules are prepared bymachine encapsulation of a slurry of the compound with an acceptablevegetable oil, light liquid petrolatum or other inert oil.

Fluid unit dosage forms for oral administration such as syrups, elixirs,and suspensions can be prepared. The water-soluble forms can bedissolved in an aqueous vehicle together with sugar, aromatic flavoringagents and preservatives to form a syrup. An elixir is prepared by usinga hydroalcoholic (ethanol) vehicle with suitable sweeteners such assugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of asuspending agent such as acacia, tragacanth, methylcellulose and thelike.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilizedbefore filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection issupplied to reconstitute the liquid prior to use. Parenteral suspensionscan be prepared in substantially the same manner except that thecompound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The preferred compositions are those adapted for oral administration.

For treatment of allergic conditions of the nose, such as rhinitis,compositions adapted for contact with nasal linings are preferred.

Compositions for inhalation are of three basic types:

(1) a powder mixture preferably micropulverized with particle sizepreferably from about 1 to about 5 microns;

(2) an aqueous solution to be sprayed with a nebulizer; and

(3) an aerosol with volatile propellant in a pressurized container.

The powders are quite simply prepared by mixing a compound of theformula with a solid base which is compatible with lung tissue,preferably lactose. The powders are packaged in a device adapted to emita measured amount of powder when inhaled through the mouth.

Aqueous solutions are prepared by dissolving the compound of the Formula1 in water and adding salt to provide an isotonic solution and bufferingto a pH compatible with inhalation. The solutions are dispersed in aspray device or nebulizer and sprayed into the mouth while inhaling.

Aerosols are prepared by dissolving a compound of the Formula 1 in wateror ethanol and mixing with a volatile propellant and placing in apressurized container having a metering valve to release a predeterminedamount of material.

The liquefied propellant employed is one which has a boiling point below65° F. at atmospheric pressure. For use in compositions intended toproduce aerosols for medicinal use, the liquefied propellant should benontoxic. Among the suitable liquefied propellants which may be employedare the lower alkanes containing up to five carbon atoms, such as butaneand pentane, or a lower alkyl chloride, such as methyl, ethyl, or propylchlorides. Further suitable liquefied propellants are the fluorinatedand fluorochlorinated lower alkanes such as are sold under thetrademarks "Freon" and "Genetron". Mixtures of the above-mentionedpropellants may suitably be employed. Examples of these propellants aredichlorodifluoromethane ("Freon 12"), dichlorotetrafluoroethane ("Freon114"), trichloromonofluoromethane ("Freon 11"),dichloromonofluoromethane ("Freon 21"), monochlorodifluoromethane("Freon 22"), trichlorotrifluoroethane ("Freon 113"), difluoroethane("Genetron 142-A") and monochlorotrifluoromethane ("Freon 13").

The term "unit dosage form", as used in the specification and claims,refers to physically discrete units suitable as unitary dosages forhuman subjects and animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic diluent, carrier or vehicle. The specifications for thenovel unit dosage forms of this invention are dictated by and directlydependent on (a) the unique characteristics of the active material andthe particular effect to be achieved and (b) the limitations inherent inthe art of compounding such an active material for use in humans andanimals, as disclosed in detail in this specification, these beingfeatures of the present invention. Examples of suitable unit dosageforms in accord with this invention are tablets, capsules, pills, coatedtablets, powder packets, wafers, granules, cachets, teaspoonfuls,tablespoonfuls, dropperfuls, ampoules, vials, aerosols with metereddischarges, segregated multiples of any of the foregoing, and otherforms as herein described.

Oral delivery systems with esters of the invention are preferred. Thecompound wherein R is hydrogen is also quite effective orally. Thosedelivery systems with solid pharmaceutical carriers can be used as anappropriate vehicle. Liquid pharmaceutical carriers can also be used asan appropriate vehicle. These liquid vehicles are separated into aqueousand non-aqueous systems. Oral unit dosage forms which are preferred aretablets, capsules, pills, and powders. Liquid carriers can be dividedinto a unit dosage by the potential recipient of the drug, for example,droppersful, teaspoonsful, tablespoonsful, and unit dosages of othermagnitude.

The ethyl ester is preferred for oral administration for its potency andduration of activity.

An effective but non-toxic quantity of the compound is employed intreatment. The dosage of the compound for treatment depends on the routeof administration and the potency of the particular compound. A dosageschedule for humans of from about 0.05 to about 10 mg. of compound in asingle dose, administered parenterally or by inhalation in thecompositions of this invention are effective for preventing allergyattacks. More specifically, the single dose is from about 0.5 to about 5mg. of compound. The oral dose is from about 0.5 to about 30 mg. in asingle dose. More specifically, the single dose is from about 1 to about20 mg. of compound. The dosage to be administered can be repeated up tofour times daily. However, when it is necessary to repeat treatment, apreferred dosage schedule reduces the secondary treatment dosage to fromabout 0.5 percent to about 20 percent of the above dosages, morespecifically, from about 1 to about 10 percent of the above dosages. Inthis manner, a state of allergy prophylaxis can be maintained. Thereduced dosage is taken until that dosage no longer provides effectiveprotection. At that time, the larger dosage is repeated, followed by thereduced dosage. An example of such a dosage schedule is the following:An asthmatic individual swallows 10 mg. of ethyl 3'-aminooxanilate. Fourhours later, the individual swallows 2 mg. of the same compound andevery four to six hours thereafter swallows 2 mg. of the same compounduntil effective asthma prophylaxis is not provided. The individual thenswallows 10 mg. of the same compound and reduces the oral dosage to 2mg. four to six hours later. The dosage schedule continues in thismanner.

The administration of the compositions of the present invention tohumans and animals provides a method for the prophylactic treatment ofallergy and anaphylactoid reactions of a reagin or non-reagin,preferably reagin, mediated nature. That is to say, these compositions,when administered to a sensitized individual prior to the time that theindividual comes into contact with substances (antigens) to which he isallergic, will prevent the allergic reaction which would otherwiseoccur. Treatment of allergy of a reagin mediated nature is preferred.

For example, the process can be used for treatment of such conditions asbronchial asthma, allergic rhinitis, food allergy, urticaria, exerciseor stress induced asthma, anaphylactoid reactions and bird fancier'sdisease. Preferred conditions for treatment are bronchial asthma,allergic rhinitis, food allergy and urticaria. More preferred conditionsare bronchial asthma and allergic rhinitis.

EXAMPLE 6

A lot of 10,000 tablets, each containing 10 mg. of ethyl3'-aminooxanilate is prepared from the following types and amounts ofingredients:

Ethyl 3'-aminooxanilate -- 100 Gm.

Dicalcium phosphate -- 1,000 Gm.

Methylcellulose, U.S.P. (15 cps) -- 60 Gm.

Talc -- 150 Gm.

Corn starch -- 200 Gm.

Magnesium stearate -- 10 Gm.

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methylcellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in preventing hay fever attacks at a dose ofone tablet every four to six hours.

EXAMPLE 7

One thousand two-piece hard gelatin capsules, each containing 5 mg. ofethyl 3'-aminooxanilate are prepared from the following types andamounts of ingredients:

Ethyl 3'-aminooxanilate -- 5 Gm.

Talc -- 150 Gm.

Magnesium stearate -- 1 Gm.

The ingredients are mixed well and filled into capsules of the propersize.

Capsules so prepared are useful in preventing attacks of bronchialasthma at a dose of one capsule every four to six hours.

EXAMPLE 8

One thousand tablets, each containing 10 mg. of ethyl 3'-aminooxanilateare prepared from the following types and amounts of ingredients:

Ethyl 3'-aminooxanilate -- 10 Gm.

Microcrystalline cellulose NF -- 410 Gm.

Starch -- 100 Gm.

Magnesium stearate powder -- 3 Gm.

The ingredients are screened and blended together and pressed intotablets.

The tablets are useful to protect against food allergy at a dose of onetablet before meals.

EXAMPLE 9

One thousand tablets, each containing 20 mg. of ethyl 3'-aminooxanilateare prepared from the following types and amounts of ingredients:

Ethyl 3'-aminooxanilate -- 20 Gm.

Microcrystalline cellulose NF -- 410 Gm.

Starch -- 100 Gm.

Magnesium stearate powder -- 3 Gm.

The ingredients are screened and blended together and pressed intotablets.

The tablets are useful to protect against urticaria at a dose of onetablet every four to six hours.

EXAMPLE 10

A sterile preparation suitable for intramuscular injection andcontaining 2 mg. of tris(hydroxymethyl)-aminomethane salt of3'-amino-oxanilic acid in each milliliter is prepared from the followingingredients:

Tris(hydroxymethyl)aminomethane salt of 3'-amino-oxanilic acid -- 2 Gm.

Benzyl benzoate -- 200 ml.

Methylparaben -- 1.5 Gm.

Propylparaben -- 0.5 Gm.

Cottonseed oil q.s. -- 1,000 ml.

One milliliter of this sterile preparation is injected for prophylactictreatment of allergic rhinitis.

EXAMPLE 11

Six hundred ml. of an aqueous solution containing 5.0 mg. of thetris(hydroxymethyl)aminomethane salt of 3'-amino-oxanilic acid per ml.is prepared as follows:

Tris(hydroxymethyl)aminomethane salt of 3'-amino-oxanilic acid -- 3 Gm.

Sodium chloride -- 5 Gm.

Water for injection q.s. -- 600 ml.

The THAM salt and sodium chloride are dissolved in sufficient water tomake 600 ml. and sterile filtered.

The solution is placed in nebulizers designed to deliver 0.25 ml. ofsolution per spray.

One spray of the solution is inhaled into the lungs every four to sixhours for prevention of asthmatic attacks.

EXAMPLE 12

A powder mixture consisting of 0.5 grams of sodio 3'-aminooxanilate andsufficient lactose to make five grams of mixture is micropulverized andplaced in an insufflator designed to deliver 50 mg. of powder per dose.

A single dose of the powder is inhaled into the lungs every four to sixhours for prevention of asthmatic attacks.

A single dose of the powder is inhaled intranasally every four to sixhours for prevention of rhinitis.

EXAMPLE 13

Twelve grams of an aerosol composition are prepared from the followingingredients:

Tris(hydroxymethyl)aminomethane salt of 3'-aminooxanilic acid -- 1.00Gm.

Freon 12 -- 1.44 Gm.

Freon 114 -- 2.16 Gm.

Water -- 6.80 Gm.

Sorbitan monoleate -- 0.60 Gm.

The THAM salt is dissolved in the water and added to the Freons. Thetwelve grams of compositions are added to a 13 cc plastic coated bottleand capped with a metering valve. The metering valve releases 80 mg. ofcomposition in an aerosol. 80 Mg. of the aerosol is inhaled every fourto six hours for prevention of asthmatic attacks.

EXAMPLE 14

In individuals who require continual treatment in the Examples 6 through13, the dosage of the Example is given initially and each succeedingadministration of the drug is at 1/50 of the initial dosage. Thismaintenance dosage is continued until effective allergy prophylaxis isnot obtained. The initial dosage of Examples 6 through 13 is thenstarted once more, followed by the maintenance dosages.

EXAMPLE 15

After allowing for the different solubilities of the compounds and theactivity of the particular compound as measured, for example, by the invivo rat passive cutaneous anaphylaxis assay, a suitable quantity ofeach of the compounds, assuming appropriate solubility, of Examples 1-5is substituted for the active compound in the compositions and uses ofExamples 6-13. Results showing anti-allergy activity are obtained.

EXAMPLE 16

The rat passive cutaneous anaphylaxis assay is run in the followingmanner:

Female Sprague-Dawley 250 gm. rats are skin-sensitized with ratanti-ovalbumin homocytotropic anti-body that is heat labile and has apassive cutaneous anaphylaxis titer of 1:128. After a 72-hour latencyperiod, the animals are challenged i.v. with 4 mg. ovalbumin (OA) + 5mg. Evans blue dye and the test compound. If the test compound isadministered orally, a solution or suspension of the test compound in0.5% methylcellulose in water is administered at an appropriate timeinterval before challenge. Thirty minutes later the extravascular bluingthat results from antigen antibody combination at the skin site is read.Antibody dilutions are used such that in control animals a 4 mm spot isthe lowest detectable spot, and 4 or 5 lower dilutions are used to givea range of antibody in each animal. Four to five animals are used foreach variable in the experiment. Percent inhibition of the PCA assay iscalculated by comparing the spot scores of treated rats with the spotscores of control rats. The spot score is the total number of detectablespots divided by the number of animals.

Ethyl 3'-aminooxanilate administered orally 20 minutes before antigenchallenge provides prophylactic inhibition of the PCA at a dosage of 5mg/kg.

It should be noted that physiologically acceptable acid addition saltsof compounds of Formula I can also be prepared and are useful in thestated utility, for example, when R is hydrogen, the acid addition saltof the 3'-amino substituent is present. Additionally, the acid additionsalt of the 3'-amino compound can be prepared when R is an alkyl group.Illustrative examples of physiologically acceptable acid addition saltsare hydrochloric, sulfuric, nitric, lauric, and cyclohexanesulfamic.

We claim:
 1. A pharmaceutical composition which comprises as the soleactive agent an anti-asthma, allergic rhinitis, food allergy orurticaria effective amount of a compound of the formula ##STR3## whereinR is hydrogen, a physiologically acceptable metal or amine cation oralkyl of one to eight carbon atoms, inclusive, or a physiologicallyacceptable acid addition salt thereof in association with apharmaceutical carrier and in the form of a tablet or capsule.
 2. Acomposition in accordance with claim 1 wherein the pharmaceuticalcarrier is solid.
 3. A composition in accordance with claim 1, wherein Ris alkyl of one to eight carbon atoms, inclusive.
 4. A composition inaccordance with claim 3 wherein the pharmaceutical carrier is a solid.5. A composition in accordance with claim 3 wherein the pharmaceuticalcarrier is a liquid.
 6. A composition in accordance with claim 5 whereinthe liquid is non-aqueous.
 7. A composition in accordance with claim 3wherein R is ethyl.
 8. A composition in accordance with claim 4 whereinR is ethyl.
 9. A composition in accordance with claim 5 wherein R isethyl.
 10. A composition in accordance with claim 6 wherein R is ethyl.11. A composition in accordance with claim 1 wherein R is hydrogen. 12.A composition in accordance with claim 11 wherein the carrier is solidand suitable for oral administration.
 13. A composition in accordancewith claim 11 wherein the carrier is liquid and suitable for oraladministration.
 14. A method of prophylactically treating reaginmediated asthma, allergic rhinitis, food allergy or urticaria whichcomprises administering to a sensitized mammal an effective amount of acompound of the formula ##STR4## wherein R is hydrogen, aphysiologically acceptable metal or amine cation, or alkyl of one toeight carbon atoms, inclusive, or a physiologically acceptable acidaddition salt thereof in association with a pharmaceutical carrier. 15.A method in accordance with claim 14 wherein the method is oral.
 16. Amethod in accordance with claim 15 wherein R is alkyl of one to eightcarbon atoms, inclusive.
 17. A method in accordance with claim 16wherein the carrier is a solid.
 18. A method in accordance with claim 16wherein the carrier is a liquid.
 19. A method in accordance with claim18 wherein the carrier is a non-aqueous liquid.
 20. A method inaccordance with claim 16 wherein R is ethyl.
 21. A method in accordancewith claim 17 wherein R is ethyl.
 22. A method in accordance with claim18 wherein R is ethyl.
 23. A method in accordance with claim 19 whereinR is ethyl.
 24. A method in accordance with claim 15 wherein R ishydrogen.
 25. A method in accordance with claim 24 wherein the carrieris solid.